The objectives of the proposed research are: 1) to study the relationship between calcium influx into heart cells and myocardial force of contraction as influenced by cyclic nucleotides; 2) to clarify the mechanisms responsible for the impaired negative chronotropic response to vagal stimulation in hyperthyroid rats. Particular emphasis will be placed on possible differences in choline uptake by synaptosomes made from brains of euthyroid and hyperthyroid rats. Using different areas of the brain from normal and thyrotoxic rats, we plan to investigate the activity of pyruvate dehydrogenase, the enzyme involved in the oxidation of pyruvate to form acetyl-CoA. The latter compound provides the acetyl group for synthesis of acetylocholine; 3) to investigate the development of super and subsensitivity to catecholamines induced by acute and chronic treatment of rats with tricyclic and non-tricyclic antidepressant drugs. Depending on the individual experiment and the informaton sought, several tissues and organ preparations will be used, including the isolated perfused rat heart, rat cerebral cortex slices, isolated rat diaphragms and synaptosomes made from rat brains. To elucidate the mechanism for reduced responsiveness to catecholamines in rats pretreated with antidepressant agents, a comparison will be made of the binding characteristics and number of beta adrenergic receptors in normal and treated animals; labeled dihydroalprenolol will be used to do these experiments.